CB4211 is our novel, refined analog of MOTS-c, a naturally occurring mitochondrial peptide discovered by Dr. Pinchas Cohen and his academic collaborators in 2012. Their research in cell-based assays and animal models indicated that MOTS-c plays a significant role in the regulation of metabolism. Certain of the original MOTS-c studies were published in an article entitled “The Mitochondrial-Derived Peptide, MOTS-c, Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance,” which appeared in the March 3, 2015 edition of the journal Cell Metabolism.
In preclinical studies conducted by CohBar, CB4211 demonstrated significant therapeutic potential for the treatment of NASH, showing improvements in triglyceride levels, as well as favorable effects on liver enzyme markers associated with NAFLD and NASH. CB4211 also demonstrated significant therapeutic potential for the treatment of obesity, demonstrating significantly greater weight loss together with more selective reduction of fat mass versus lean mass in comparison to a market-leading obesity drug in DIO mice. The therapeutic effects of CB4211 have been further evaluated in the well-established Stelic Animal Model (STAM™) of NASH. In this model, treatment with CB4211 resulted in a significant reduction of the non-alcoholic fatty liver disease activity score, or NAS, a composite measure of steatosis (fat accumulation), inflammation and hepatocyte ballooning (cellular injury). Data from these studies were presented at the American Association for the Study of Liver Disease (AASLD) 2017 Liver Meeting® in October, 2017.
In addition to the therapeutic potential indicated by the preclinical models described above, data were presented at the 2018 American Diabetes Association meeting providing in vitro evidence that CB4211 inhibits adipocyte lipolysis, a process that is foundational in the development of liver steatosis, through an insulin-dependent mechanism. This data provides a potential mechanistic explanation for previous observations in vivo, including efficacy of CB4211 in animal models of NASH, and antisteatotic effects on livers of mice on a high fat diet, where a corresponding reduction in circulating fat and biomarkers of liver damage was also observed. The activity of CB4211 appears to involve sensitizing insulin action on the insulin receptor.
In November 2019, we announced the completion of the Phase 1a portion of the clinical trial, with the drug being well-tolerated, and the commencement of the recruiting phase of the final Phase 1b stage of the study. Currently, this clinical trial is temporarily paused due to the COVID-19 pandemic.
CB5138 Analogs for Fibrotic Diseases: Our discovery efforts have identified a family of novel peptides, CB5138 analogs, and we have demonstrated anti-fibrotic and anti-inflammatory effects in vitro in human cells and in vivo in prophylactic and therapeutic models of IPF. In these models, CB5138 analogs have resulted in the significant reduction in lung fibrosis, inflammation, and collagen levels. In in vitro cell cultures, a CB5138 analog also decreased the production of pro-collagen in cultured human fibroblasts, and inhibited the process of conversion of healthy lung epithelial cells to pathological pro-fibrotic cells.
CB5064 Analogs for COVID-19 Associated ARDS and Type 2 Diabetes: In May, the company initiated testing of CB5064 analogs that interact with the apelin receptor in preclinical models of ARDS to assess their potential as therapeutics for COVID-19 associated ARDS. CohBar previously demonstrated the beneficial effects of this novel family of peptides on glucose tolerance, insulin sensitivity, and weight loss in an obese mouse model of T2D, as presented at the American Diabetes Association in 2019.
MBT5 Analogs (CXCR4 Antagonists) for Cancer and Other Disease Indications: We have identified a family of novel potent and selective peptide inhibitors of CXCR4, MBT5 analogs. Analogs of MBT5 have demonstrated high potency at nanomolar levels in in vitro studies of CXCR4 inhibition in cultured cells. In a difficult to treat in vivo animal model of melanoma, the B16F10 syngeneic tumor model, an analog of MBT5 showed enhanced antitumor activity in combination with the chemotherapeutic agent temozolomide.
MBT3 Analogs for Cancer Immunotherapy: We have identified a novel family of peptides, MBT3 analogs, that enhance the killing of cancer cells by human immune cells. An analog of MBT3 produced a highly significant reduction in the number of cancer cells in the presence of peripheral blood mononuclear cells (PBMCs), including T cells, B cells and NK cells.
Our discovery efforts have resulted in the identification of more than 100 previously unidentified peptides encoded within the mitochondrial genome and we have generated over 1,000 analogs. We continue to explore the broad biological effects of these peptides and their potential application as novel therapeutics. Our criteria include examining MDP analogs with the greatest commercial and therapeutic potential, the most suitable development and clinical resources, and the broadest intellectual property protection and exploitation opportunities.